High doses of cisplatinum have shown substantial activity in metastatic melanoma. Interferon-alpha is another active agent in this disease and has been shown to potentiate the cytotoxicity of platinum in vitro. Interleukin-2 (IL-2) in combination with interferon-alpha has synergistic antitumor activity in animal models and appears to mediate responses through activation of the host immune system. Since animal models have demonstrated synergistic anti-tumor activity when agents with direct cytotoxic effects are combined with immunomodulators, we combined interferon-alpha/platinum with interferon-alpha/IL-2 in an attempt to improve the therapeutic outcome in metastatic melanoma patients. Interferon-alpha 5 mu/m2 was administered subcutaneously on days 0-3, 7-10, 15-18 and 22-25. Cisplatinum (100 mg/m2 in the first 4 patients, 75 mg/m2 in the next 5 patients) was infused over 30 minutes in hypertonic saline on days 1 and 8. IL-2 was given on days 15-18 and 22-25 by continuous infusion at a dose of 3 mu/m2/d (total 96 hours of infusion for each week). A bolus of IL-2 (3 mu/2) was given prior to the infusion on day 15 and 22, and additional boluses (1.5 mu/m2) were given on days 16-18 and 23-25. Three of 9 evaluable patients responded in adrenal, skin, lung, and lymph node sites. Toxicity was excessive and included intolerable nausea and vomiting, fatigue, creatinine elevation, myelosuppression, confusion, pruritus, and transaminase elevation. Although responses were noted, there was no indication that a high rate of complete responses could be achieved, and toxicity was too severe to justify continued patient accrual.